4YM9

Crystal structure of Porcine Pancreatic Elastase (PPE) in complex with the novel inhibitor JM102

4YM9 の概要

• エントリーDOI: 10.2210/pdb4ym9/pdb
• 分子名称: Chymotrypsin-like elastase family member 1, 2-ethyl-2-(hydroxymethyl)-N-(6-methylpyridin-3-yl)butanamide, SULFATE ION, ... (7 entities in total)
• 機能のキーワード: porcine pancreatic elastase, inhibitor, hydrolase
• 由来する生物種: Sus scrofa (Pig)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 27055.95

構造登録者

Hofbauer, S.,Brito, J.A.,Mulchande, J.,Nogly, P.,Pessanha, M.,Moreira, R.,Archer, M. (登録日: 2015-03-06, 公開日: 2016-06-29, 最終更新日: 2024-10-16)

主引用文献

Ruivo, E.F.,Goncalves, L.M.,Carvalho, L.A.,Guedes, R.C.,Hofbauer, S.,Brito, J.A.,Archer, M.,Moreira, R.,Lucas, S.D.
Clickable 4-Oxo-beta-lactam-Based Selective Probing for Human Neutrophil Elastase Related Proteomes.
ChemMedChem, 11:2037-2042, 2016

PubMed Abstract: Human neutrophil elastase (HNE) is a serine protease associated with several inflammatory processes such as chronic obstructive pulmonary disease (COPD). The precise involvement of HNE in COPD and other inflammatory disease mechanisms has yet to be clarified. Herein we report a copper-catalyzed alkyne-azide 1,3-dipolar cycloaddition (CuAAC, or 'click' chemistry) approach based on the 4-oxo-β-lactam warhead that yielded potent HNE inhibitors containing a triazole moiety. The resulting structure-activity relationships set the basis to develop fluorescent and biotinylated activity-based probes as tools for molecular functional analysis. Attaching the tags to the 4-oxo-β-lactam scaffold did not affect HNE inhibitory activity, as revealed by the IC50 values in the nanomolar range (56-118 nm) displayed by the probes. The nitrobenzoxadiazole (NBD)-based probe presented the best binding properties (ligand efficiency (LE)=0.31) combined with an excellent lipophilic ligand efficiency (LLE=4.7). Moreover, the probes showed adequate fluorescence properties, internalization in human neutrophils, and suitable detection of HNE in the presence of a large excess of cell lysate proteins. This allows the development of activity-based probes with promising applications in target validation and identification, as well as diagnostic tools.

PubMed: 27465595
DOI: 10.1002/cmdc.201600258

実験手法

X-RAY DIFFRACTION (1.8 Å)